Project Summary/Abstract The United States is amidst an epidemic of opioid overdose, including opioid analgesics, heroin, and illicitly- manufactured fentanyl and related synthetic opioids. Multiple interventions to address opioid overdose have been employed, such as lay access to naloxone to reverse opioid overdose, yet the number of people dying each year from opioid overdose continues to increase each year. In addition to efforts to reduce mortality, efforts are needed to reduce the occurrence of any opioid overdose, particularly given the rapidity of synthetic opioid overdoses, which may restrict the time available to intervene once an overdose occurs. Opioid stewardship activities, necessary to avert yet another generation affected by the opioid epidemic, may paradoxically contribute to the illicit opioid epidemic, and expanded access to opioid use disorder treatment, while essential, is limited by resources, stigma, and the willingness of patients to accept the intervention. The NIDA-funded pilot study of REBOOT (repeated dose behavioral intervention to reduce opioid overdose), a motivational interviewing-based brief intervention addressing experienced and witnessed overdose events, resulted in substantial reductions in the occurrence of any opioid overdose, as well as the number of opioid overdoses that occurred during 16 months of follow-up. This full trial of REBOOT includes two regions of the United States ? San Francisco, largely unaffected by the fentanyl epidemic ? and Boston, at the epicenter of fentanyl use, overdose, and mortality. REBOOT will enroll 300 persons with opioid use disorder who are currently using opioids, have previously received take-home naloxone, and are at high-risk for recurrent overdose. Participants will be randomized to the intervention or attention-control and seen every four months for 16 months, with interval assessments for overdose events, overdose risk factors, engagement in substance use disorder treatment, and substance use. Medical records will be reviewed to capture unreported overdose events, including death. Results will determine if addressing overdose through motivational interviewing can reduce the occurrence of overdose, contributing to efforts to respond to this national emergency.